Preparation of optically active 2-halopropionic acids

ABSTRACT

The present invention relates to a process for the preparation of optically active 2--halopropionic acids, in which the corresponding optically active alkyl 2--halopropionates are caused to react with a carboxylic acid at elevated temperature in a transacylation reaction with the formation of the optically active 2--halopropionic acid and the alkyl carboxylate, and the optically active 2--halopropionic acid obtained is separated from the reaction mixture. The optically active products produced are important intermediates for the preparation of plant protectants and pharmaceuticals.

The present invention relates to a novel process for the preparation ofoptically active 2-halopropionic acids.

It is known to be possible to prepare l-2-chloropropionic acid and thesodium salt thereof by alkaline hydrolysis of isobutyll-2-chloropropionate. During this process however, a poor-qualityproduct (ca 90 to 95 % of excess enantiomer) is often formed, whichstill contains 5 to 10 % of lactic acid as by-product.

FR 2,700,164 describes the synthesis of l-2-chloropropionates by causingo-silylized silylized ketenacetals to react with N-chlorosuccinimide andthe hydrolysis thereof with alkali metal hydroperoxides to forml-2-chloropropionic acid.

JP 57/094295, JP 62/205797, EP-A 196,625, JP 61/111699 reveal that it ispossible to dissociate racemic 2-chloropropionates enantio-selectivelyby means of enzymes. However, a disadvantage of this is, apart from themaximum possible yield of only 50 % - based on racemate -, theinsufficient enantiomer purity of the 2-chloropropionates formed.

The racemate dissociation of 2-halocarboxylates by lipase from candidacylindracea is also known (US 898,972).

According to Bio. Med. Chem. Lett. 1991 1 339, optically activephenoxypropionates are obtained by enzymatic esterification of thecorresponding racemic acids, one of the enantiomers being esterifiedwhilst the other remains as acid, depending on the enzyme used.Separation of the optically active compounds is then carried out bydistillation and/or extraction. Depending on process conditions usedconcentrations of the d- or l-isomers of from 70 % to ca 95 % areobtained.

In the case of enzymatic dehalogenation of racemic chloropropionic acid,the d-enantiomer is converted into lactic acid and the l-chloropropionicacid remains unchanged. The maximum possible yields are approximately 50% --based on racemate --(Biocatalysis, D.A. Abramowicz CZ (Ed) vanNostrand R. N.Y. (1990), Journal of General Microbiology 128, 1755(1982)).

Furthermore, EP-A 257,716 discloses a continuous process in which methyld,l-2- bromopropionate is used as racemate and is converted into methyll-(-)-2- bromopropionate by means of Candida cylindracea lipase in atwo-phase system.

However no hydrolysis products are isolated in this process.

Moreover S. K. Dahod and P. Sinta-Mangano in Biotechnol. Bioeng. 30 (8),995 (1987) describe the lipase-catalyzed hydrolysis of methyll-2-chloropropionate in the presence of carbon tetrachloride. Thedisadvantage of this method is, apart from the use of a chlorinatedsolvent, the low yield of ca 30 % at an enantiomer purity of only 95 %.

In addition, EP-A 511,526 describes a process for the enzymatichydrolysis of racemic 2-chloropropionates in a two-phase systemcomprising water and a substantially water-immiscible organic solventfor the ester. This process is very elaborate, since the organic phasemust a number of times be separated, brought into contact with thehydrolase, and recycled. Since only incomplete conversion takes placeand no enantiomer-pure products are obtained despite relative longreaction times, this method is unsuitable for commercial manufacture ofl-2- chloropropionic acid and the sodium salt thereof.

Other processes for the preparation of optically active 2-halocarboxylicacids are racemate dissociations of 2-halocarboxamides withmicroorganisms such as pseudomones (DE 4,117,255 A1) and2-halocarboxylic acid nitrites by means of microorganisms (Pure andAppl. Chem. 62, 1441 (1990)).

Thus the object of the present invention is to provide a simple processfor the preparation of optically active 2-halopropionic acids having ashigh a chemical 25 and optical purity as possible (at least ca 98 %excess enantiomer).

Accordingly, we have found a process for the preparation of opticallyactive 2- halopropionic acids, wherein the corresponding opticallyactive alkyl 2-halopropio- nates are caused to react with a carboxylicacid at elevated temperature in a transacylation reaction with theformation of the optically active 2-halopropionic acid and the alkylcarboxylate, and the optically active 2-halopropionic acid obtained isseparated from the reaction mixture.

The process of the invention is described with reference to thefollowing reaction equation ##STR1## In which I is the optically activealkyl 2-halopropionate in which X denotes halogen, II is the carboxylicacid, III is the optically active 2-halopropionic acid obtained, and IVis the alkyl carboxylate formed during transacylation.

Generally, in the optically active alkyl 2-halopropionates I and2-halopropionic acids III, X denotes chlorine, bromine, or iodine,preferably chlorine or bromine and more preferably chlorine.

In the reaction equation given above R1 generally denotes C1 -C8 alkyl,preferably C1 -C6 alkyl, and R2 generally denotes hydrogen or C1 -C4alkyl.

The carboxylic acids II used are advantageously formic acid, aceticacid, and propionic acid, preferably formic acid or acetic acid and morepreferably formic acid.

The preparation of the optically active alkyl 2-halopropionates to beused as starting product is advantageously carried out starting from thecorresponding optically active lactates by halogenation thereof. Forexample, the preparation of alkyl l-2-chloropropionates is carried outby halogenation of the corresponding alkyl d-lactates by replacing thehydroxyl group by chlorine. The alkyl d-lactates may be chlorinated inknown manner (cf eg EP-A 401,104, JP 61/057534 (1986), JP 02/104560(1990), JP 61/068445 (1986) and FR-A 2,459,221). The chlorination ispreferably carried out using thionyl chloride in the presence of acatalyst such as N,N-dimethylformamide, inversion taking place at theasymmetrical C atom. The crude product is separated from thehigh-boiling fractions and then purified by distillation.

Using the procedure described above, isobutyl l-2-chloropropionate, forexample, can be obtained having a chemical purity of ca 98 to 99.8 %.The optical purity (l:d) is approximately 98:2 to 100:0 %.

To effect the transacylation of the invention, the optically activealkyl 2- halopropionates may alternatively be used without previouspurification.

The reaction for the preparation of the optically active 2-halopropionicacids is advantageously carried out at temperatures ranging from 40 dcto 200 dc, preferably from 80 dc to 150 dc and very advantageously atthe boiling point of the carboxylic acid used for transacylation or atthe boiling point of the alkyl carboxylate formed during transacylation.

The reaction can be carried out under reduced, standard, or elevatedpressure. It is general to operate at pressures ranging from 0.1 to 10bar, preferably from 0.5 to 3 bar.

The carboxylic acid to be used for the transacylation can be used in thestoichiometric amount based on alkyl 2-halopropionate used. Preferablyhowever, the carboxylic acid is used in excess, generally an excess of10% to 5000%, preferably 200% to 1000%.

The carboxylic acid can be initially present together with the alkyl 2-halopropionate or alternatively it can be added during thetransacylation reaction 20 or a portion thereof can be initially presentand the remainder added during the transacylation reaction.

It may be advantageous to carry out the reaction in the presence of anacid catalyst. Suitable acid catalysts are, eg, mineral acids such asphosphoric acid, hydrohalic acids, sulfuric acid, organic sulfonic acidssuch as p-toluenesulfonic acid, ion exchangers in hydrogen form, andLewis acids. Sulfuric acid is particularly suitable generally, thecatalysts are used in amounts ranging from 0.1 wt% to 10 wt%, based onthe alkyl 2-halopropionate.

It may also be advantageous to add small amounts of water during thetransacylation reaction, generally amounts ranging from 0 wt% to 50 wt%,preferably from 0.01 wt% to 30 wt%, based on the alkyl 2-halopropionate,whilst the amount of water can be less or can be entirely omitted whenuse is made of formic acid as carboxylic acid, since formic acid partlydecomposes under the 3s reaction conditions with the formation of water.Most of the water is usually separated concomitantly with the removal,by distillation, of the alkyl carboxylate formed.

The process is usually carried out without the use of added solvent, butsolvents which are inert under the reaction conditions such aschlorinated hydrocarbons, aliphatic hydrocarbons such as hexane, oraromatic hydrocarbons such as toluene and xylene may be used as diluentsif desired.

It may be advantageous to separate the alkyl carboxylate formed duringtransacylation during the reaction at the rate at which it is formed,advantageously by distillation.

Purification of the reaction mixture to effect isolation of theoptically active 2- halopropionic acid is usually carried out byfractional distillation. This is carried out for example by separatingthe alkyl carboxylate formed during transacylation and any carboxylicacid still present from the reaction mixture by removal by distillation,thus obtaining the optically active 2-halopropionic acid as residue. Thecrude product obtained as residue can then be isolated as pure productby further purification, advantageously by distillation.

The distillations described above may be carried out under standardpressure conditions, in vacuo, or under superatmospheric pressure. Ifthe transacylation is carried out using acid catalysts, the acidcatalysts are advantageously separated or neutralized prior todistillation, eg, by the addition of alkali metal or alkaline earthmetal hydroxides or alkali metal salts of weaker acids such as alkalimetal formates and alkali metal acetates such as sodium formate andsodium acetate.

In the transacylation of the invention the optically active2-halopropionic acids are obtained in a very economical manner in highyield and high optical purity.

During the synthesis and purification steps, the optical purity isretained or is only slightly reduced. The optically active2-chloropropionic acids are starting materials in synthesis processesfor pharmaceuticals and plant protectants, eg, in synthesis processesfor optically active aryloxypropionic acids such as d-2,4-dichlorophen-oxypropionic acid, d-2-methyl-4-chlorophenoxypropionic acid, butyl-2-(4-5- (trifluoromethyl)-2-pyridinyl!oxy)phenoxy propionate(Fluazifopbutyl), and ethyl-2- 4-(6-chloro-2-benzoxazolyl)oxy!phenoxy!propionate (Fenoxaprop-ethyl).

The following examples illustrate the invention.

Example1

493.5 g (3.0 mol ) of isobutyl l-2-chloropropionate (d: 0.8 % l: 99.2 %)and 138 g (3.0 mol) of formic acid (100% strength) are placed in a flasktogether with 5.6 g (0.057 mol) of sulfuric acid (100 % strength). Asolution of 552 g (12 mol) of formic acid (100 % strength) and 5.6 g(0.057 mol) of sulfuric acid (100 % strength) is metered in under reflux(112°C.) over a period of 3 h. Via a column, an azeotrope comprisingisobutyl formate, formic acid and water is simultaneously distilled offfrom the reaction flask. On completion of the addition, stirring of thereaction solution is continued for a further 2 h at the boil. Onremoval, by distillation, of the said azeotrope, the temperature risesto 115°C. The material in the reaction flask is neutralized with 15.5 g(0.228 mol) of sodium formate and then fractionally distilled. There areobtained 308.6 g of l-2-chloropropionic acid (d: 0.8 % l: 99.2 %) havinga degree of purity of 99.8 % (GC) bp₄₀ : 102° C.; equivalent to a yieldof 94.6 % of theory.

Example 2

493.5 g (3.0 mol) of isobutyl l-2-chloropropionate (d: 0.8 % l: 99.2 %)and 138 g (3.0 mol) of formic acid (100 % strength) are placed in aflask together with 5.6 g (0.057 mol) of sulfuric acid (100% strength).A solution of 306.7 g (6 mol) of is formic acid (90 % strength) and 5.6g (0.057 mol) of sulfuricacid(100% strength) is metered in under reflux(112° C.) over a period of 3 h. Via a column, an azeotrope comprisingisobutyl formate, formic acid and water is simultaneously distilled offfrom the reaction flask. On completion of the addition, stirring iscontinued for a further 2 hours at the boil and distillation continued.During this phase, the temperature rises to 115° C. The material in thereaction flask is neutralized with 15.5 g (0.228 mol) of sodium formateand then fractionally distilled. There are obtained 305.4 g of l-2-chloropropionic acid (d: 0.9% l: 99.1 %) having a degree of purity of99.9 % (GC) bp₄₀ : 102° C.; equivalent to a yield of 93.7 % of theory.

Example 3

329 g (2.0 mol) of isobutyl l-2-chloropropionate (d: 0.8 % l: 99.2 %)and 230 g (5.0 mol) of formic acid (100 % strength) are placed in aflask together with 3.4 g (0.035 mol) of sulfuric acid (100 % strength).A solution of 360 g (10 mol) of formic acid (100 % strength) and 3.4 g(0.035 mol) of sulfuric acid (100 % strength) is metered in under reflux(112° C.) over a period of 3.5 h. Via a column, an azeotrope comprisingisobutyl formate, formic acid and water is simultaneously distilled offfrom the reaction flask. On completion of the addition, stirring iscontinued for a further 2 hours at the boil and distillation continued.During this phase, the temperature rises to 116° C. The material in thereaction flask is neutralized with 9.52 g (0.14 mol) of sodium formateand then fractionally distilled. There are obtained 205 g of l-2-chloropropionic acid (d: 0.9% l: 99.1 %) having a degree of purity of99.8 % (GC) bp₃₂ : 97° C.; equivalent to a yield of 94.3 % of theory.

Example 4

164.5 g (1.0 mol) of isobutyl l-2-chloropropionate (d: 0.8% l: 99.2 %)and 333 g (5.0 mol) of acetic acid (90 % strength) are placed in a flasktogether with 3.68 g (0.036 mol) of sulfuric acid (96% strength). 6669(10 mol) of aqueous acetic acid (90 %) are metered in over a period of 6hours at 110° C. to 115° C. At the same time, an azeotrope comprisingisobutyl acetate and water is distilled off from the reaction flask viaa column. The material in the reaction flask is then neutralized with5.9 g (0.072 mol) of sodium acetate and fractionally distilled. Thereare obtained 100 g of l-2-chloropropionic acid (d: 1 .0 % l: 99.0 %)having a degree of purity of 99.8 % (GC) bp₅₄ : 107° C.; equivalent to ayield of 92.0 % of theory.

Example 5

3299 (2.0 mol) of isobutyl l-2-chloropropionate (d: 0.8 % l: 99.2 %) and625 g (10 mol) of acetic acid (96 % strength) are placed in a flasktogether with 11 g (0.108 mol) of sulfuric acid (96% strength). 666 g(10 mol) of aqueous acetic acid (90 % strength) are metered in over aperiod of 7.5 hours at 114° C. to 120° C. At the same time, an azeotropecomprising isobutyl acetate and water is distilled off from the reactionflask via a column. Stirring is then continued for a further 2.5 hoursat 120° C. and azeotrope is distilled off. The remaining reactionmixture is neutralized with 17.7 g (0.216 mol) of sodium acetate andfractionally distilled. There are obtained 206.89 of l-2-chloropropionic acid (d: 1.0% l: 99.0 %) having a degree of purity of99.7 % (GC) bp₄₇ : 104° C.; equivalent to a yield of 95.0 % of theory.

Example 6

122.5 g (1 mol) of methyl d-2-chloropropionate (d: 99% l: 1 %) and 138 g(3 mol) of formic acid (100 % strength) are placed in a flask togetherwith 5.5 g (0.054 mol) of sulfuric acid (96% strength). A solution of300 g (3.5 mol) of formic acid (100 % strength) and 2.9 g (0.0284 mol)of sulfuric acid (96 % strength) is metered in under reflux (102° C.)over a period of 75 minutes. Via a column, an azeotrope comprisingmethyl formate, formic acid and water is simultaneously distilled offfrom the reaction flask. On completion of the addition, stirring iscontinued for half an hour at the boil and distillation continued.During this phase, the temperature rises to 106° C. The material in thereaction flask is neutralized with 11.2 g (0.165 mol) of sodium formateand then fractionally distilled. There are obtained 193 g ofd-2-chloropropionic acid (d: 99% l: 1 %) having a degree of purity of99.4% (GC), bp₆₂ : 109° C.; equivalent to a yield of 94.4 % of theory.

We claim:
 1. A process for the preparation of optically active2-halopropionic acids, wherein the corresponding optically active alkyl2-halopropionates are caused to react with a carboxylic acid at elevatedtemperature in a transacylation reaction with the formation of theoptically active 2-halopropionic acid and the alkyl carboxylate, and theoptically active 2-halopropionic acid obtained is separated from thereaction mixture.
 2. A process as defined in claim 1, wherein thereaction is carried out at temperatures ranging from 40° C. to 200° C.3. A process as defined in claim 1, wherein the optically active2-halopropionic acid obtained is separated from the reaction mixture byseparating the alkyl carboxylate formed during transacylation and anycarboxylic acid still present from the reaction mixture by distillation,thus obtaining the optically active 2-halocarboxylic acid as bottoms. 4.A process as defined in claim 1, wherein the reaction is carried out atthe boiling point of the carboxylic acid used for the transacylation orat the boiling point of the alkyl carboxylate formed duringtransacylation.
 5. A process as defined in claim 1, wherein the alkylcarboxylate formed during transacylation is distilled off.
 6. A processas defined in claim 1, wherein the reaction is carried out underpressures ranging from 0.1 to 10 bar.
 7. A process as defined in claim1, wherein the optically active 2- halopropionic acid obtained isisolated from the reaction mixture formed after transacylation bysubjecting the reaction mixture to fractional distillation.
 8. A processas defined in claim 1 , wherein the carboxylic acid is used in excess.9. A process as defined in claim 1, wherein the reaction is carried outin the presence of an acid catalyst.
 10. A process as defined in claim1, wherein a solvent which is inert under the reaction conditions isadditionally used.
 11. A process as defined in claim 1, which is usedfor the preparation of optically active 2-chloropropionic acids.